Chiral synthesis of pyrrolidine core compounds en route to neuronal nitric oxide synthase inhibitors

Abstract

A chiral synthesis of pyrrolidine compounds en route to selective neuronal nitric oxide synthase inhibitors, and representative inhibitor compounds heretofore unattainable.

We claim: 
     
       1. A method of preparing a chiral (aminopyridinyl)alkyl-substituted pyrrolidine core compound, said method comprising:
 providing a racemic di-N-Boc-protected 3,4-trans-(aminopyridinyl)alkyl-substituted pyrrolidine alcohol; 
 protecting said amino group of said (aminopyridinyl)alkyl-substituent with a Boc reagent, to provide a tri-Boc-protected pyrrolidine compound; and 
 resolving said racemic trans-alcohol by camphanic acid esterification, to provide separable cis-diastereorners. 
 
     
     
       2. The method of  claim 1  wherein said pyrrolidine alcohol is substituted with a (4-methylpyridin-2-yl)methyl moiety. 
     
     
       3. The method of  claim 1  wherein said pyrrolidine alcohol is protected with a silyl chloride reagent before said amino group protection. 
     
     
       4. The method of  claim 3  wherein said alcohol protection is removed before said camphanic acid esterification. 
     
     
       5. The method of  claim 1  comprising base hydrolysis of one said enantiomer of said racemate, to provide a chiral 4-hydroxypyrrolidine compound. 
     
     
       6. The method of  claim 5  wherein said 4-hydroxypyrrolidine compound is allylated. 
     
     
       7. The method of  claim 6  comprising oxidation of said allyl moiety of said chiral pyrrolidine compound to provide an aldehyde group, and reductive amination of said aldehyde group with an ethanamine. 
     
     
       8. The method of  claim 1  comprising concurrent removal of three Boc-protecting groups.